Aquaporin 7 (AQP7), the gateway protein controlling glycerol release, has recently emerged as a modulator of adipocyte metabolism. AQP7 knockout mice develop obesity and hyperglycemia. The contribution of AQP7 to these abnormalities in humans is unknown. We examined whether common single nucleotide polymorphisms (SNPs) in the AQP7 gene modulate the risk of obesity and related abnormalities. Among several SNPs we identified, A-953G in the AQP7 promoter was associated with type 2 diabetes in 977 (530 female/447 male) Caucasians: odds ratio for XG (i.e., AG+GG) versus AA individuals was 1.36 (95% CI 1.01-1.84), P = 0.04. This finding was entirely due to the association among females (1.8 [1.2-2.6], P = 0.004), which was no longer significant when adjusted for BMI. In fact, BMI was higher in XG than in AA females (30.8 +/- 6.6 vs. 28.9 +/- 5.2, P = 0.002). This association was confirmed in independent case-control study (n = 299 female subjects) for morbid obesity (1.66 [1.01-2.74], P = 0.04). Luciferase and mobility shift assays showed that, compared with -953A, the -953G promoter had reduced transcriptional activity (P = 0.001) and impaired ability to bind CCAAT/enhancer binding protein (C/EBP)beta transcription factor (P = 0.01). Finally, AQP7 expression in adipose tissue decreased from AA to AG to GG individuals (P = 0.036). These data strongly suggest that AQP7 downregulation is pathogenic for obesity and/or type 2 diabetes.